Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers the State University of NJ, Newark, NJ 07103, USA. eliseo.eugenin@rutgers.edu.

Abstract

Neoplastic growth and cellular differentiation are critical hallmarks of tumor development. It is well established that cell-to-cell communication between tumor cells and "normal" surrounding cells regulates tumor differentiation and proliferation, aggressiveness, and resistance to treatment. Nevertheless, the mechanisms that result in tumor growth and spread as well as the adaptation of healthy surrounding cells to the tumor environment are poorly understood. A major component of these communication systems is composed of connexin (Cx)-containing channels including gap junctions (GJs), tunneling nanotubes (TNTs), and hemichannels (HCs). There are hundreds of reports about the role of Cx-containing channels in the pathogenesis of cancer, and most of them demonstrate a downregulation of these proteins. Nonetheless, new data demonstrate that a localized communication via Cx-containing GJs, HCs, and TNTs plays a key role in tumor growth, differentiation, and resistance to therapies. Moreover, the type and downstream effects of signals communicated between the different populations of tumor cells are still unknown. However, new approaches such as artificial intelligence (AI) and machine learning (ML) could provide new insights into these signals communicated between connected cells. We propose that the identification and characterization of these new communication systems and their associated signaling could provide new targets to prevent or reduce the devastating consequences of cancer.

Cartoon denoting the main aspects of deep learning algorithms and artificial intelligence (AI) in biology. As described in the text, critical points include the input information, the features selected for analysis, the training of the AI, the numbers of layers or variables or classifiers, as well as the desired output. The unbiased connection between the different clusters or layers of the AI system will provide the best predictors for associated gene/mRNA/protein for a particular biomarker. If this biomarker is unknown, the clusters can select the dysregulated pathways or better treatments based on the input information. Thus, the possibilities are endless.

Representation of the potential role of gap junctions (GJs), hemichannels (HCs), and tunneling nanotubes (TNTs) in carcinogenesis. GJs and TNTs are expressed in a localized manner to help the tumor to invade neighboring tissues. Tumor cells (stem cells and cancer cells) communicate between them and surrounding cells (stromal healthy cells, immune cells) through TNTs and GJs, transferring organelles and metabolic agents from cancer stem cells and immune cells to stromal healthy cells. (1) An open-ended TNT allows the exchange of organelles (mitochondria), vesicles, and small molecules between the connected cells. (2) The open-ended TNT contains Cx protrusions that allow the exchange of small molecules, such as Ca2+ or inositol triphosphate (IP3), between connected cells.

TNTs enable the transfer of protective agents to cancer cells that are susceptible to radiation and chemical treatment. (A) Using a silicon coculture system as described, T98G (glioblastoma, resistant to radiation and temozolomide (TMZ) treatment) and U87MG cells (glioblastoma, sensible to radiation and TMZ treatment) were cocultured to examine survival. Upon removal of the silicon barrier, both cell types could form TNTs and communicate with each other. (B) Quantification of the survival of T98G and U87 cells alone (back line and red line, respectively) and cocultured U87 cells (blue line). In this case, T98G cells are more resistant to radiation than U87 cells (0 to 12 Gy). However, upon coculturing and the subsequent formation of TNTs, T98G cells transfer the radiation resistance to U87 cells (blue line). The transfer of resistance was dependent on TNT formation, because the use of latrunculin (latrun), a TNT blocker, prevented the transfer of resistance into U87 cells (pink line). Thus, the TNT formation transfers a protective agent against radiation treatment from T98G to U87 cells. Thus, TNTs are essential to spreading chemical and radiation resistance into surrounding cells.